tbuckley/cabot-search huggingface dataset:
Molecular characterization of the tumor microenvironment in chromophobe renal cell carcinoma (ChRCC) and related oncocytic neoplasms.
Authors: Chris Labaki, Long Zhang, Yue Hou, Kevin Bi, Charbel Hobeika, Ziad Bakouny, Sabrina Yvonne Camp, Carmen Priolo, Damir Khabibullin, Nicholas Schindler, Michel Alchoueiry, Thomas Denize, Renee Maria Saliby, Sayed Matar, Sabina Signoretti, Eliezer Mendel Van Allen, Sachet A. Shukla, David A. Braun, Elizabeth Henske, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2022)

4549 Background: ChRCC represents about 5% of all kidney cancer and has a dismal prognosis in the metastatic setting, with limited response to immune checkpoint inhibitors (ICI) and targeted therapy. We evaluated the molecular properties of ChRCC and related oncocytic neoplasms to define the tumor immune microenvironment and identify potential therapeutic strategies. Methods: ChRCC, renal oncocytoma (RO) and low-grade oncocytic tumor (LOT) samples with matched normal kidney specimens were evaluated using single-cell RNA sequencing (scRNA-seq) and single-cell T-cell receptor sequencing (scTCR-seq). T-cell antigenic specificities from scTCR-seq were inferred using a comprehensive database of annotated T-cell receptor sequences (VDJdb). The infiltration of CD45+ immune cells in renal oncocytic tumors and ccRCC samples was quantified using immunohistochemistry (IHC). Bulk RNA-sequencing (RNA-seq) data of clear cell RCC (ccRCC) and ChRCC were further analyzed using The Cancer Genome Atlas (TCGA) KIRC and KICH cohorts, respectively, with immune cell fractions calculated using CIBERSORTx. Results: After quality-control, 46,817 cells from 5 tumor (ChRCC: n = 3, RO: n = 1 and LOT: n = 1) and 4 normal samples were isolated for scRNA-seq analysis. Renal oncocytic tumors (ChRCC, RO, and LOT) had a low density of CD45+ cells (mean: 739 ± 114 cells/mm 2 ; n = 5) compared to ccRCC (mean: 3,420 ± 1,979 cells/mm 2 ; n = 5) (p &lt; 0.05). Across all tumors, CD8+ T-cell clusters displayed a low expression of immune exhaustion markers (i.e. PDCD1 [PD-1], CTLA4, LAG3, HAVCR2 [TIM-3], and TIGIT). Analysis of TCGA bulk RNA-seq data after adjustment for CD8 T-cell fraction showed no difference in the expression of most immune exhaustion markers (i.e. PDCD1, CTLA4, LAG3) in ChRCC compared to normal samples (p &gt; 0.05), contrasting with a substantially higher expression in ccRCC versus normal kidney (p &lt; 0.05). Analysis of the T-cell repertoire (scTCR-seq) of ChRCC, RO and LOT samples did not identify a pattern of clonal expansion, and a considerable proportion of clonotypes were inferred to have specificity for viral antigens (range: 1.3 to 34.4% among all samples; 11.3 to 34.4% after filtering out two samples with a low ( &lt; 300) number of T-cells). Conclusions: Renal oncocytic tumors, including ChRCC, exhibit a low infiltration of immune cells, a non-exhausted immune phenotype and, a lack of clonally expanded tumor-specific T-cells. These findings may partially explain the molecular basis for the lack of response to ICIs in advanced ChRCC and outline the unique exhaustion phenotype of renal oncocytic tumors.
Hepatic arterial infusion chemotherapy versus trans-arterial chemoembolization in unresectable hepatocellular carcinoma: A systematic review and meta-analysis.
Authors: Azizullah Beran, Ziad Abuhelwa, Waleed Abdulsattar, Abdurahman Alloghbi, Ali Alqahtani, Danae M. Hamouda
Journal: Journal of Clinical Oncology (2022)

e16141 Background: Trans-arterial chemoembolization (TACE) has been one of the standard options for patients with unresectable hepatocellular carcinoma (HCC). Recent studies have shown that liver arterial infusion chemotherapy (HAIC) has favorable outcomes in these patients, but its use has been limited due to the need for technical expertise. In this systematic review and meta-analysis, we compared the efficacy and safety of HAIC vs. TACE for unresectable HCC. Methods: We performed a comprehensive literature search of PubMed, Embase, and Cochrane databases through January 12, 2022, for all peer-reviewed studies that compared the outcomes of HAIC vs. TACE in patients with large, unresectable HCC. Our primary outcomes were the objective response rate (ORR), disease control rate (DCR), and progressive disease (PD). The secondary outcomes were overall survival (OS), progression-free survival (PFS), and grade ≥3 adverse events (AEs). Pooled risk ratio (RR) and hazard ratio (HR) with the corresponding 95% confidence intervals (CIs) were obtained by the Mantel-Haenszel method within a random-effect model. Heterogeneity was assessed using the Higgins I 2 index. Results: Six studies (one randomized controlled trial [RCT], two non-randomized trials, and three retrospective cohort studies) were eligible for final analysis. A total of 899 patients were included for the final evaluation. HAIC was associated with significantly higher ORR (RR 2.70, 95% CI 2.06-3.55, P &lt; 0.001, I 2 = 10.1%) and DCR (RR 1.42, 95% CI 1.19-1.70, P &lt; 0.001, I 2 = 54.5%) and substantially reduced PD (RR 0.55, 95% CI 0.40-0.75, P &lt; 0.001, I 2 = 56.6%) compared to TACE. The median OS was significantly longer in the HAIC group, ranging from 11.4 to 23.1 months vs. TACE, ranging from 4 to 16.1 months (HR 0.49, 95% CI 0.28-0.85, P = 0.01 I 2 = 84.7%). The median PFS was significantly longer in the HAIC group, ranging from 5.5 to 9.6 months, vs. TACE, ranging from 1.5 to 5.4 months (HR 0.45, 95% CI 0.26-0.79, P = 0.001, I 2 = 84.6%). Notably, the incidence of grade≥3 AEs was lower in the HAIC group than in TACE (RR 0.61, 95% CI 0.47-0.80, P &lt; 0.001, I 2 = 16.4%). Conclusions: Compared to TACE, HAIC significantly improved ORR, DCR, and OS in unresectable HCC with a significantly better safety profile. However, our meta-analysis is hampered by the limited number of studies. Future large-scale multicenter RCTs are warranted to further evaluate the outcomes of HAIC vs. TACE in the management of unresectable HCC.
Response to epithelial growth factor receptor inhibitor (EGFRi) treatment in patients with early-onset, treatment-naïve metastatic colorectal cancer (mCRC): An ARCAD database analysis.
Authors: Zhaohui Jin, Jesse G. Dixon, Joleen M. Hubbard, Cathy Eng, Christopher Hanyoung Lieu, Jean-Yves Douillard, Richard Adams, Timothy S. Maughan, Eric Van Cutsem, Alan P. Venook, Heinz-Josef Lenz, Volker Heinemann, Sebastian Stintzing, Richard S. Kaplan, Carsten Bokemeyer, Benoist Chibaudel, John Raymond Zalcberg, Takayuki Yoshino, Aimery De Gramont, Qian Shi
Journal: Journal of Clinical Oncology (2022)

3572 Background: Early onset colorectal cancer (eoCRC: disease diagnosed &lt; 50) has been increasing over the past 2 decades. Currently, standard treatment recommendations for eoCRC patients (pts) with metastatic disease does not differ from late-onset CRC (loCRC) pts although outcomes data in eoCRC pts is limited. Methods: Individual patient data on 5,761 treatment-naive metastatic eoCRC pts was pooled from 8 phase II and III randomized EGFRi studies (2000 - 2012) from the ARCAD mCRC database. The distribution of demographics, clinicopathological features, and biomarkers were summarized by age groups. Progression-free survival (PFS) was compared between age groups by stratified Cox models, adjusting for potential confounders. Predictive value of age group was evaluated by testing interaction effect between treatment and age variables based on a subset of trials with concurrent randomizations between regimens with and without EGFRi Results: eoCRC (n=756) were more evenly distributed between gender, had improved performance status (PS), increased likelihood of metastatic resection, and distant lymph node metastasis, but were less likely to have lung metastasis or KRAS mutation compared to loCRC (n=5,005, table 1). eoCRC and loCRC patients had similar distribution of primary tumor sidedness, primary resection, liver and/or peritoneal involvement, number of metastatic sites involved, and BRAF mutations (MT). No difference in PFS for eoCRC versus loCRC pts was noted (7.8 vs. 7.9 months [M], adjusted hazard ratio [HR adj ], 1.02, 95% confidence interval [CI], 0.93-1.11). Among pts with KRAS wild type (WT) and left sided primary tumors, univariable analysis of EGFRi demonstrated improved mPFS in loCRC (9.9 vs 8.5M, HR = 0.74, p&lt;0.001), but this benefit was not seen in eoCRC (8.3 vs 8.9 months, HR 1.20, p=0.36). The same pattern was observed upon multivariable analysis (Table). Conclusions: In our pooled analysis, EGFRi + chemotherapy significantly improved PFS in treatment-naïve loCRC patients but not in left sided, KRAS WT, eoCRC patients. Further validation in an independent cohort is warranted. [Table: see text]
Mapping the epidemiologic characteristics of cancer patients with NTRK gene fusions: A real-world analysis of the Cerner Enviza Eletronic Health Records (EHR) database.
Authors: Haris G. Vikis, Otavio Clark, Martina Furegato, Nathan Vavroch, Stacey Purinton, Tom Haskell, Tasha Boshears
Journal: Journal of Clinical Oncology (2022)

e15123 Background: Fusions in neurotrophic-tropomyosin receptor kinase (NTRK) genes occur in a vast array of tumors and are among the most important genetic alterations in cancer patients. Their presence warrants the use of specific agnostic therapy (AT) with TRK inhibitors Larotrectinib (L) and Entrectinib (E). AT is associated with high levels of tumor response rate in patients showing NTRKgenetic alterations. This mutation is rare and the epidemiologic profile and clinical characteristics of NTRK positive patients are not completely clear. Methods: Our aim was to identify and describe the characteristics of patients with NTRK fusions in a large EHR database. De-identified records of NTRK positive oncologic patients were retrieved from Cerner-Enviza EHR, a healthcare provider network with 100 different providers across the USA, between November 2018 to August 2021. Data extracted were primary tumor, gender, age, and treatment received. Results: We identified 123 patients with NTRK alterations. Major primary tumor locations are described in the table. Males were 56% of the population, median age at diagnosis was 59 years, 36% of the patients were treated with E and 64% with L. Conclusions: In this sample, NTRK mutations were more common in patients with Lung Cancer and Soft Tissue tumors. The median age at diagnosis was 59 years.[Table: see text]
Antibiotic therapy and association with oncological outcomes from targeted and immune-based therapy in hepatocellular carcinoma (HCC).
Authors: David J. James Pinato, Xiaoxue Li, Pallavi Shruti Mishra-Kalyani, Antonio D'Alessio, Claudia A.M. Fulgenzi, Guo Wei, Julie A. Schneider, Donna Rivera, Richard Pazdur, Marc Robert Theoret, Sandra J. Casak, Steven Lemery, Ibilola Fashoyin, Alessio Cortellini, Lorraine Cheryl Pelosof
Journal: Journal of Clinical Oncology (2022)

4089 Background: Immune checkpoint inhibitors (ICI) alone or in combination with tyrosine kinase (TKI) or VEGF pathway inhibitors (VEGFi) are therapeutic options in unresectable HCC (uHCC). Whether exposure to antibiotics (ATB), a consolidated adverse prognostic factor in ICI recipients, affects outcome in HCC remains unclear. Methods: FDA analysed patient-level data of 4098 patients receiving ICI (n = 842) either as monotherapy (n = 258) or combinations (n = 584), TKI (N = 1968), VEGFi (n = 480) or placebo (n = 808) as part of 9 international clinical trials submitted to the US Food and Drug Administration in support of marketing applications. Associations for ATB exposure within 30 days before or after initiation of anti-cancer treatment (ATB) with overall (OS) and progression-free survival (PFS) were examined across therapeutic modality. Estimates were weighted by propensity score (PSW) using clinically relevant covariates. Results: Out of 4098 patients with uHCC mostly secondary to Hepatitis B (39%) or C (21%) infection, the majority were males (83%) with a median age of 64 (range 18-88), ECOG performance status of 0 (60%) and Child-Pugh A class (98%). Most patients had metastases (68%) but did not have macrovascular invasion (71%). Overall, 620 patients (15%) were ATB+, with comparable rates across placebo (12%), TKI (16%), VEGFi (15%), and ICI (16%). In the overall population, ATB was associated with shorter PFS (2.8 vs 3.9 months [m], HR 1.29, 95%CI 1.22-1.36) and OS (6.4 vs. 8.8 m; HR 1.36, 95%CI 1.29-1.43). In PSW analyses, ATB was associated with shorter PFS in patients treated with ICI (HR 1.52, 95%CI 1.34-1.73), TKI (HR 1.29, 95%CI 1.19-1.39) and placebo (HR 1.23, 95%CI 1.11-1.37). Similar results were observed in PSW analyses of OS in patients treated with ICI (HR 1.22, 95%CI 1.08-1.38), TKI HR 1.40, 95%CI 1.30-1.52), and placebo (HR 1.40, 95%CI 1.25-1.57). Consistent outcomes were observed for ATB+ patients within ICI treatment subgroups, including patients treated with anti-PD-1 monotherapy (PFS HR 1.49, 95%CI 1.22-1.80; OS HR 1.31 1.02-1.68) and ICI combinations (PFS HR 1.50, 95%CI 1.26-1.77; OS HR 1.14 0.99-1.32). Conclusions: Unlike other oncological indications where the detrimental effect of ATB may be more prominent in ICI recipients, ATB is associated with inferior outcomes across a broad range of anti-cancer therapies for HCC and placebo. Whether ATB is causally linked to worse outcomes through disruption of the gut liver axis remains to be demonstrated in translational studies.
Randomized phase II trial of neoadjuvant androgen deprivation therapy plus abiraterone and apalutamide for patients with high-risk localized prostate cancer: Pathologic response and PSMA imaging correlates.
Authors: Diogo Assed Bastos, Rafael Coelho, Leonardo Cardili, Felipe Galiza, Eder Nisi Ilario, Públio Viana, Claudio Bovolenta Murta, Giuliano Guglielmetti, Mauricio Cordeiro, Jose Pontes Jr, David Queiroz Borges Muniz, Jamile Almeida Silva, Jose Mauricio Mota, Guilherme Fialho de Freitas, Katia Ramos Moreira Leite, Carlos Alberto Buchpiguel, William Carlos Nahas
Journal: Journal of Clinical Oncology (2022)

5085 Background: Patients (pts) with high-risk localized prostate cancer (HRLPC) have a significant risk of disease recurrence and metastasis after radical prostatectomy (RP). Neoadjuvant therapy remains investigational but there may be a role for the next-generation androgen signaling inhibitors. We sought to evaluate pathologic and imaging response after the intense neoadjuvant approach. Methods: This is a phase II investigator-initiated randomized trial of 3-month neoadjuvant therapy with goserelin (androgen deprivation therapy, ADT) + abiraterone acetate and prednisone (AAP arm) or AAP + apalutamide (A-APA arm) before RP for pts with HRLPC (Gleason ≥ 8 and/or cT3N0-1 and/or PSA ≥ 20 ng/mL). The primary endpoint was the rate of pathologic complete response (pCR) or minimal residual disease (MRD, tumor ≤ 0.5 cm). The secondary endpoints were safety, rate of residual cancer burden ≤0.25 cm 3 (RCB = tumor volume x cellularity), Gallium 68 prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/magnetic resonance correlates and rate of biochemical relapse (BR). Results: Sixty-two pts were randomized to A-APA (N = 31) or AAP (N = 31). Median age was 65 (range 47-77) years. NCCN risk groups included high-risk disease in 19%, very high-risk in 76% and regional (N1) disease in 5% (79% cT3, 65% Gleason 8-10, 57% PSA ≥ 20 ng/mL). Outcomes after intense neoadjuvant ADT are described in the Table. There was no statistically significant difference between study arms regarding pCR/MRD or RCB ≤ 0.25 cm 3 rates. Patients with complete PSMA-PET response (psmaCR) demonstrated a RCB ≤ 0.25 cm 3 rate of 50% compared to 7.5% in pts without a psmaCR ( P= 0.001). The rate of BR was 14% for pts with RCB ≤ 0.25 cm 3 versus 38% in pts with RCB &gt; 0.25 cm 3 ( P= 0.118). At current median follow-up of 2.6 years, all patients with both psmaCR and RCB ≤ 0.25cm 3 (N = 11, 18%) are free of BR. There were 2 grade (G) 5 adverse events (AEs) in the AAP arm (pulmonary embolism and sudden death, both after surgery). Nine (14.5%) pts (6 in A-APA; 3 in AAP) experienced G3-4 treatment-related AEs. The most common G3-4 AEs were hypertension (11.3%), AST/ALT elevations (3.2%) and skin rash (1.6%). Conclusions: No difference in pCR or MRD was observed between arms. Although pCR or MRD after intense neoadjuvant ADT was infrequent, a significant proportion of pts achieved a favorable pathologic response with RCB ≤ 0.25 cm 3 . PSMA-PET response is a potential surrogate for pathologic response. Clinical trial information: NCT02789878. [Table: see text]
Evaluation of the use of COVID-19 vaccines in patients treated with immunotherapy.
Authors: Yun Man, Garrett Rompelman, Angela Chen, Anita Giobbie-Hurder, Elizabeth Iannotti Buchbinder
Journal: Journal of Clinical Oncology (2022)

e18781 Background: Immunotherapy can boost a patient’s immune system to bring about anti-tumor activity and may theoretically exaggerate the inflammatory immune response to infection or vaccinations. Conversely, vaccination may enhance immune activity in patients on immunotherapy. Currently, there are limited safety data in patients treated with immunotherapy who received COVID-19 vaccines. Methods: An IRB-approved retrospective review of Dana-Farber Cancer Institute patients treated with PD-1 checkpoint inhibitors and received COVID-19 vaccines was performed. The primary endpoint was the incidence rate of immune-related adverse events (irAEs) pre- and post- COVID-19 vaccinations. An Electronic Health Record search identified all patients who completed COVID-19 vaccines between 12/1/2020 and 3/31/2021 and received anti-PD-1 monotherapy between 10/1/2020 and 5/31/2021. Medical record review identified timing, occurrence, and grading of irAEs as defined by clinicians or Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Results: A total of 229 patients were included in the study. The most common underlying cancers were lung (32%) and melanoma (26%). The majority of patients had Pfizer-BioNTech COVID-19 vaccine; 64% of all patients received the third dose of vaccine. The median duration of treatment was 15 months, and median duration of follow-up was 19 months. Among the study cohort, 120 irAEs occurred before vaccination (any grade); 30 (25%) were grade 1, 35 (29%) were grade 2, 11 (9%) were grade 3 or 4, and 44 (37%) were ungraded. The main types of irAEs were skin toxicities (37% of all irAEs) followed by thyroid dysfunction (22%) and colitis (11%). Of the 75 irAEs that occurred after vaccination, 24 (32%) were grade 1, 16 (21%) were grade 2, 16 (21%) were grade 3 or 4, and 19 (26%) were ungraded. The main irAEs types were skin toxicity (31% of all irAEs) followed by thyroid dysfunction (13%) and hepatic toxicity (12 %). The all-grade pre- and post-vaccine irAE incidence rates per 100 patient-months were 4.13 and 5.09, respectively. Within this cohort, there were 0.96 (95% CI -0.362-2.284, p = 0.15) more irAEs post vaccine per 100 patient-months of anti-PD-1 therapy. Conclusions: The data weakly suggested that there is a higher incidence of irAEs post COVID-19 vaccine; however, the comparison did not achieve statistical significance. Further analysis of other patient characteristics will help to determine if any specific patterns are observed.[Table: see text]
Quantitative analysis of spatial distribution of lymphocytes in hepatocellular carcinoma: A biomarker correlated with survival and gene expression in cancer immune system.
Authors: Hong-Seok Lee, Kyungdoc Kim, Guhyun Kang, Kyu-Hwan Jung, Ahmed Omar Kaseb, Sunyoung S. Lee
Journal: Journal of Clinical Oncology (2022)

4119 Background: Tumor microenvironment (TME) is known to impact prognosis in hepatocellular carcinoma (HCC). Although digital pathology and artificial intelligence have been adopted in modern medicine and oncology, few quantitative biomarkers have been identified to predict the prognosis and guide treatment for HCC via an automated analysis of TME at the cellular level. Methods: Histopathological images and clinical data of 365 cases with HCC were obtained from TCGA (The Cancer Genome Atlas), and 60 of HCC pathology images and cancer lesion annotations were collected from PAIP2019 [1]. DenseNet-based HCC segmentation model (F1-score, 0.904) and Hover-Net-based cell detection model (F1-score, 0.914) were developed using PAIP2019 and MoNuSac datasets, respectively [2,3,4]. Each histopathology image of TME was segmented via the segmentation model into two areas: 1) non-tumoral regions that include the stroma; 2) tumoral regions where HCC cells are concentrated. The cell detection model recognized individual cells on images, specified lymphocytes, and calculated ratios of lymphocyte to total cell count (RLTCC) in segmented regions. RLTCC was then correlated with clinical survival outcomes, HCC primary risk factors, and RNA expression profiles. Results: RLTCC in tumoral regions was not significantly associated with prognosis. Patient groups with higher RLTCC in non-tumoral regions (RLTCC in NT) showed better overall survival (OS) than those with lower RLTCC in NT regardless of HCC risk factors (median OS 45.7 vs 18.6 months; log hazard ratio of -1.6 ± 1.1, p=0.006). These patients had significantly enriched expression of genes (p&lt;0.05) related to cancer antigen presentation (higher gene expression by +33.7%), recognition of cancer cells by T-cell (+32.0%), T-cell priming and activation (+32.2%), immune cell localization to tumors (+31.9%), and killing of cancer cells (+24.7%). Those with HCC etiology of hepatitis B and C had more patients in the higher RLTCC in NT (17/21 patients, 81.0%; 23/29, 79.3%, respectively). In comparison, those with alcohol consumption showed equal distribution (26/53, 49.1%). The RLTCC in NT in hepatitis B/C groups was statistically higher than alcohol consumption group (p&lt;0.05). Conclusions: A digital prognostic biomarker, RLTCC in NT of TME was identified as a significant prognostic indicator, and it was shown to correlate with RNA gene expression related to T-cell mediated cancer immunity. A retrospective analysis of clinical response from systemic therapy in relation to digital biomarkers is underway and will be reported. References: [1] Kim et al. Med. Image Anal. 67 (2021). [2] Riasatian, Abtin, et al. Med. Image Anal. 70 (2021). [3] Graham, Simon, et al. Med. Image Anal. 58 (2019). [4] Verma, Ruchika, et al. IEEE Trans Med Imaging 39.1380-1391 (2020).